Lung cancer provides an ideal paradigm for investigating gene-environmental interactions. Although a majority of lung cancer victims are tobacco users, the unresolved paradox is that only a minority of long-term heavy smokers will develop the disease. Therefore, genetically determined susceptibility is likely an important component in lung cancer development. We plan to examine the role of the alpha1AD gene in lung cancer risk. This is a logical step because individuals who are either homozygous or heterozygous (carriers) for the alpha1AD allele are predisposed to the development of chronic obstructive pulmonary disease (COPD). COPD is a risk factor for lung cancer and shares common risk factors with lung cancer, such as cigarette smoking and familial aggregation. Thus, we hypothesize that alpha1AD allele carriers have an increased risk for lung cancer. The proposed case-control study is designed to test this hypothesis. As secondary hypotheses, we will test whether the association between lung cancer risk and alpha1AD carrier status varies by history of tobacco smoke exposure, COPD, histopathologic type of the tumor, and family history of cancer. Twelve hundred cases with primary lung cancer who are newly diagnosed (from April 1997 to September 2001) at Mayo Clinic will be recruited as the case group. Twelve hundred population-based controls (matched by age, gender, and race) will be assembled for testing the hypothesis that alpha1 AD carriers are at a higher lung cancer risk. Approximately twelve hundred full siblings from 600 lung cancer cases will be included as an ethnicity-matched control group to eliminate the bias due to population admixture (as observed in our pilot study). Data will be collected from medical records, patient interview, and self-administered questionnaires. Alpha1-antitrypsin (a protease inhibitor, Pi) allele type will be determined by isoelectric focusing assay. Statistical analyses include multiple logistic regression models for case-population control comparisons and a newly developed multivariate score statistic will be used for case-sibling control comparisons. This study will allow us to evaluate the roles of 1) a common gene that is associated with lung tissue damage, 2) tobacco smoke (carcinogen) exposure, and 3) COPD that shares common risk factors with lung cancer and often occurs before the onset of lung cancer. Results from this study will lead to further understanding of the biologic basis of lung cancer development and progression, may uncover an additional marker for identifying high-risk individuals, and could provide additional impetus for targeted behavior modification, chemo-prevention, and gene therapy programs.